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Genetics of Progeria
Introduction Progeria, also known as Hutchinson- Gilford progeria syndrome, is a rare and severe autosomal dominant genetic disorder characterized by accelerating aging in young children. It occurs as a new mutation in approximately 1 per 8 million births. Children diagnosed with progeria have small, fragile bodies with a large head, wrinkled skin, prominent eyes and visible scalp veins. Very few patients exceed age 13; 90% of patients with progeria die from complications, such as atherosclerosis related stroke and myocardial infarction (3,4). Signs and Symptoms Children with progeria began developing symptoms during the first few months of life. The first symptoms include localized scleroderma and failure to thrive. Scleroderma is the hardening and tightening of the skin and failure to thrive refers to the low weight-gain rate. As the child reaches age two, they have limited growth and full-body hair loss, while developing a small face with a recessed jaw and pinched nose. As the child ages, they develop wrinkled skin, kidney failure, atherosclerosis, poor eye sight, and cardiovascular disease. Progeria can cause musculoskeletal degeneration, which leads to the loss of body fat and muscle, hip dislocations, and stiff joints. Although there are many aging features associated with progeria, patients do not experience neurodegeneration and do not show any cancer predisposition or wear and tear conditions, such as degenerative joint disease (3). Genetics Progeria is due to a mutation in the LMNA gene. Children without progeria have a normal LMNA gene with 12 exons. This gene codes for prelamin A, a structural protein important for the integrity of cell membranes. Prelamin A has a CAAX- box motif at the carboxyl-terminus, which contains a farnesyl functional group. The farnesyl group assists with prelamin A's temporary attachment to a cell's nuclear rim. Once attached, the farnesyl group is removed via farnesylation. Prelamin A then undergoes an internal proteolytic cleavage, which removes the last 18 amino acids, converting prelamin A to lamin A. Lamin A, along with lamin B and lamin C, is a main component that makes up the nuclear lamina of cells (2). Children with progeria have a mutation in the LMNA gene. The mutation changes glycine GGC to glycine GGT in the 608th codon in exon 11. Although this is a silent mutation, it activates a new cryptic splice site by creating a better match. This results in splicing within exon 11, removing 150 nucleotides from the end of the exon. The prelamin A will still contain the CAAX-box, which will allow the removal of the farnesyl group, however, the internal proteolytic cleavage will not occur. The mutation also eliminates an essential phosphorylation site. The removal of the proteolytic cleavage and phosphorylation site creates a long filament called progerin, which can interact with lamin C and create heterodimeric multiprotein filaments. This disrupts the structural components, leading to nuclear instability. The instability leads to the premature aging seen in progeria (1,2,3). Studies There are many studies being done to better understand progeria. In one study, fibroblasts from patients with progeria and their parents were tested with immunofluorescent antibodies against lamin A/C. This test showed there were structural nuclear abnormalities in 48% of the patients with progeria compared with less than 6% of their parent's normal cells. With further testing and analysis, the lymphocytes of children with progeria had strange nuclear sizes and shapes along with chromatin extrusion and envelope disruption. The lamin A expression in those cells was 25% of that from the normal control cells. This breakthrough discovery allowed researchers to pinpoint lamin A mutations as the cause of progeria (2). Treatments and Screening If progeria is suspected in a child due to hallmark physical symptoms, a genetic test can be performed to detect the mutation. The genetic testing allows for an earlier diagnosis, which can allow the doctor to provide earlier symptomatic treatment, which can improve a child's quality of life. Theoretically, there is a way to screen for the mutation in the LMNA gene while the fetus is still in the womb, however, due to the rarity and sporadic nature of the disease, it is not practical at this time because there is no way to tell which children are at risk. Even if screening is performed, the benefit is limited due to the lack of treatment. However, many couples with a child previously affected with progeria may the fear recurrence, in which case LMNA testing can be valuable (2,5). Although there are no treatments for progeria, children can be treated for the complications of the disorder, such as using aspirin or bypass surgery to treat cardiovascular disease. Recently, researchers have published cell and mouse studies that point to farnesyltransferase inhibitors (FTIs) as potential drugs for progeria treatment. These drugs help better attach farnesyl groups to the prelamin A, which allows them to attachment more permanently to the nuclear rim. This can reverse cell structure abnormalities caused by the mutation. More studies and clinicial trials have to be done on the drug before it is released, however, it gives great promise for a treatment in the future (3,5). References 1. Phenotype and Course of Hutchinson–Gilford Progeria Syndrome. New England Journal of Medicine. 2. Hutchinson–Gilford progeria syndrome. Wiley Online Library. 3. Progeria. Wikipedia. 4. Hutchinson-Gilford progeria syndrome. Genetics Home Reference. 5. Progeria. NIH.